Grape Seed Extract

Grape seed extract was first prepared by Jack Masquelier in 1947. Its early reputation was for its effect on the permeability of small blood vessels, and it was used to strengthen fragile capillaries ^{35Reference 35Weseler et al. · 2017Masquelier’s grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefitsView study →}.

Blood pressure is the most replicated human finding. A meta-analysis of 16 RCTs (810 subjects) found GSE reduced systolic blood pressure by ~6.1 mmHg and diastolic by ~2.8 mmHg, with larger effects in younger, obese, and metabolic-syndrome subjects ^{2Reference 2Zhang et al. · 2016Meta-analysisThe impact of grape seed extract treatment on blood pressure changes: a meta-analysis of 16 randomized controlled trialsView study →}.

An earlier meta-analysis of 9 trials (390 subjects) found a smaller fall in systolic pressure (~1.5 mmHg) and in heart rate, with no effect on diastolic pressure ^{3Reference 3Feringa et al. · 2011Meta-analysisThe effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trialsView study →}.

A more recent dose- and duration-stratified meta-analysis of 19 trials found a significant diastolic reduction (~2.2 mmHg) and heart-rate reduction, but systolic effects were non-significant and highly heterogeneous, with a non-linear dose-response ^{4Reference 4Foshati et al. · 2022Meta-analysisThe effect of grape (Vitis vinifera) seed extract supplementation on flow-mediated dilation, blood pressure and heart rate: a systematic review and meta-analysis with duration- and dose-response analysisView study →}.

Individual RCTs are consistent with modest benefit. 300 mg/day improved blood pressure and perceived stress in healthy volunteers ^{6Reference 6Schön et al. · 2021RCTGrape seed extract positively modulates blood pressure and perceived stress: a randomized, double-blind, placebo-controlled study in healthy volunteersView study →} and ambulatory BP in pre-/stage-I hypertension ^{7Reference 7Ras et al. · 2013Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertensionView study →}. In prehypertensive Japanese adults, 400 mg/day of a grape seed proanthocyanidin extract lowered systolic BP by ~13 mmHg over 12 weeks ^{8Reference 8Odai et al. · 2019RCTEffects of grape seed proanthocyanidin extract on vascular endothelial function in participants with prehypertension: a randomized, double-blind, placebo-controlled studyView study →}.

A 300 mg/day beverage was tested in pre-hypertension ^{9Reference 9Park et al. · 2016Effects of grape seed extract beverage on blood pressure and metabolic indices in individuals with pre-hypertensionView study →} and an acute 300 mg dose blunted the exercise pressor response in prehypertensive men ^{10Reference 10Kim et al. · 2018Grape seed extract supplementation attenuates the blood pressure response to exercise in prehypertensive menView study →}.

A controlled trial in athletes also reported improved brachial flow-mediated dilation with chronic GSE supplementation ^{17Reference 17Nho et al. · 2022Effects of grape seed extract supplementation on endothelial function and endurance performance in basketball playersView study →}.

Gap: systolic effects are inconsistent across trials (I² > 90%), populations and extracts differ widely, and most trials run only 4–12 weeks — long-term and hard-outcome data are absent.

A systematic review and meta-analysis of controlled trials found GSE supplementation significantly reduced malondialdehyde (a lipid-peroxidation marker) and oxidised LDL, with a marginal rise in total antioxidant capacity ^{1Reference 1Foshati et al. · 2021Meta-analysisThe effect of grape seed extract supplementation on oxidative stress and inflammation: a systematic review and meta-analysis of controlled trialsView study →}.

In a crossover RCT in heavy smokers, a standardised procyanidin extract (catechin and epicatechin monomers plus dimers) reduced LDL susceptibility to oxidation ^{12Reference 12Vigna et al. · 2003Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokersView study →}, and a red grape seed extract lowered oxidised LDL in mild hyperlipidemia ^{11Reference 11Razavi et al. · 2013Clinical trialRed grape seed extract improves lipid profiles and decreases oxidized low-density lipoprotein in patients with mild hyperlipidemiaView study →}.

In cardiac surgery, GSE given before coronary bypass reduced oxidative-stress and reperfusion-injury markers comparably to vitamin C ^{14Reference 14Safaei et al. · 2017Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgeryView study →}.

Free gallic acid and galloylated flavanols contribute to the radical-scavenging profile ^{31Reference 31Bagchi et al. · 2014Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overviewView study →}.

Gap: the biomarker improvements are consistent, but no trial has shown that lowering oxidation markers translates into fewer events or slower disease progression.

A large meta-analysis (50 trials) reported significant reductions in total cholesterol (~6 mg/dL), LDL cholesterol (~5 mg/dL), and triglycerides (~6.6 mg/dL) with GSE, but no change in HDL ^{5Reference 5Asbaghi et al. · 2020Meta-analysisThe effects of grape seed extract on glycemic control, serum lipoproteins, inflammation and body weight: a systematic review and meta-analysis of randomized controlled trialsView study →}.

The earlier cardiovascular-risk meta-analysis found no significant lipid effect ^{3Reference 3Feringa et al. · 2011Meta-analysisThe effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trialsView study →}. Small RCTs in mild-to-moderate hyperlipidemia reported improved lipid profiles and raised serum paraoxonase (an HDL-associated antioxidant enzyme) activity with 200 mg/day red grape seed extract ^{11,13Reference 11Razavi et al. · 2013Clinical trialRed grape seed extract improves lipid profiles and decreases oxidized low-density lipoprotein in patients with mild hyperlipidemiaView study →Reference 13Argani et al. · 2016Clinical trialThe effect of red grape seed extract on serum paraoxonase activity in patients with mild to moderate hyperlipidemiaView study →}.

The effect sizes are small, and the trials are short.

The oxidative-stress/inflammation meta-analysis found a significant reduction in high-sensitivity C-reactive protein (hsCRP) ^{1Reference 1Foshati et al. · 2021Meta-analysisThe effect of grape seed extract supplementation on oxidative stress and inflammation: a systematic review and meta-analysis of controlled trialsView study →}, and the glycemic/lipid meta-analysis likewise reported lower CRP with GSE ^{5Reference 5Asbaghi et al. · 2020Meta-analysisThe effects of grape seed extract on glycemic control, serum lipoproteins, inflammation and body weight: a systematic review and meta-analysis of randomized controlled trialsView study →}.

In a human NAFLD RCT, GSE (250 mg proanthocyanidins) reduced interleukin-6 (IL-6) and malondialdehyde versus placebo ^{15Reference 15Ghanbari et al. · 2024Grape seed extract supplementation in non-alcoholic fatty liver diseaseView study →}.

The effect is attributed to suppression of NF-κB signalling by the flavanol fraction ^{31Reference 31Bagchi et al. · 2014Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overviewView study →}.

The human readout is limited to a few circulating markers, mixed across them; broader cytokine and tissue-level effects are inferred from preclinical work.

In animals, grape seed proanthocyanidins reduced dimethylnitrosamine-induced liver damage ^{18Reference 18Shin et al. · 2010AnimalThe proanthocyanidins inhibit dimethylnitrosamine-induced liver damage in ratsView study →}, attenuated hepatic injury in streptozotocin-diabetic rats ^{19Reference 19Mansouri et al. · 2014AnimalAntioxidant effects of proanthocyanidin from grape seed on hepatic tissue injury in diabetic ratsView study →}, and reversed high-fat/fructose-diet steatosis comparably to metformin ^{20Reference 20Yogalakshmi et al. · 2013AnimalGrape seed proanthocyanidin rescues rats from steatosis: a comparative and combination study with metforminView study →}.

In humans, two 2-month randomised placebo-controlled trials in NAFLD patients reported improved oxidative-stress markers and quality of life ^{15Reference 15Ghanbari et al. · 2024Grape seed extract supplementation in non-alcoholic fatty liver diseaseView study →} and improvements in metabolic factors and steatosis severity ^{16Reference 16Ghanbari et al. · 2024Clinical trialThe effects of grape seed extract supplementation on cardiovascular risk factors, liver enzymes and hepatic steatosis in patients with non-alcoholic fatty liver diseaseView study →} — both small (n≈50), single-centre and from overlapping research groups, with no histological or long-term hepatic outcomes.

The 50-trial meta-analysis found GSE reduced fasting plasma glucose (~2 mg/dL) but did not change HbA1c ^{5Reference 5Asbaghi et al. · 2020Meta-analysisThe effects of grape seed extract on glycemic control, serum lipoproteins, inflammation and body weight: a systematic review and meta-analysis of randomized controlled trialsView study →}. An acute pilot showed GSE with a high-carbohydrate meal blunted postprandial glycemia in healthy participants, consistent with in-vitro inhibition of intestinal α-glucosidase and pancreatic α-amylase by the proanthocyanidins ^{24Reference 24Sapwarobol et al. · 2012Postprandial blood glucose response to grape seed extract in healthy participants: a pilot studyView study →}.

Gap: the fasting-glucose effect is small and the absence of any HbA1c change argues against meaningful long-term glycemic benefit; dedicated diabetic-outcome trials are absent.

Grape seed extract is used as a phlebotonic for chronic venous insufficiency, but GSE-specific human data are sparse. The 2020 Cochrane review of phlebotonics found the class probably reduces oedema slightly, but only one of its 56 quantified trials used grape seed extract — most of the moderate-certainty evidence comes from rutosides and other agents, not GSE ^{21Reference 21Martinez-Zapata et al. · 2020Systematic reviewPhlebotonics for venous insufficiencyView study →}.

A small pilot using 4D-flow MRI suggested GSPE plus compression stockings improved venous blood-flow velocity in CVI more than stockings alone ^{22Reference 22Jung et al. · 2022Clinical trialPilot study on the effect of grape seed proanthocyanidin extract on inferior vena cava blood flow in patients with chronic venous insufficiency using 4D flow MRIView study →}, and a rat model showed GSPE improved lymphatic drainage and perfusion in secondary lymphedema ^{23Reference 23Cheon et al. · 2025Grape seed proanthocyanidins improve lymphatic drainage and blood perfusion in secondary lymphedema modelsView study →}.

Gap: direct human evidence for grape seed specifically (as opposed to the phlebotonic class) is thin — one small pilot and a fraction of a Cochrane review; the lymphedema signal is animal-only.

Grape seed polyphenols inhibit amyloid-β aggregation and oligomerisation in vitro and, in transgenic mouse models of Alzheimer’s disease, reduce cerebral amyloid deposition and attenuate inflammation ^{25Reference 25Wang et al. · 2009AnimalConsumption of grape seed extract prevents amyloid-beta deposition and attenuates inflammation in brain of an Alzheimer’s disease mouseView study →}.

A five-month study in Tg2576 mice specifically lowered the memory-impairing Aβ*56 oligomer ^{26Reference 26Liu et al. · 2011AnimalGrape seed polyphenolic extract specifically decreases Aβ*56 in the brains of Tg2576 miceView study →}.

Fractionation work shows catechin- and epicatechin-derived species drive the anti-aggregation activity ^{27Reference 27Hayden et al. · 2015Inhibiting amyloid β-protein assembly: size-activity relationships among grape seed-derived polyphenolsView study →}, and the same extract class inhibits tau fibrillisation, relevant to tauopathies ^{28Reference 28Pasinetti et al. · 2010Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathiesView study →}.

A registered Phase 2 trial of a grape-seed anti-oligomeric extract was terminated (NCT02033941), so no human efficacy readout exists.

Gap: all efficacy data are preclinical; the one human trial was terminated, and brain bioavailability of orally dosed OPCs in humans is uncertain.

Grape seed proanthocyanidins show chemopreventive activity in cell and animal models, but no completed human efficacy trial. In rats, dietary proanthocyanidin reduced azoxymethane-induced colonic preneoplastic lesions with decreased proliferation and increased apoptosis ^{29Reference 29Nomoto et al. · 2004Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosisView study →}.

In colon-cancer models GSPs suppressed tumour angiogenesis by downregulating VEGF and angiopoietin-1 ^{30Reference 30Huang et al. · 2012Grape seed proanthocyanidins inhibit colon cancer-induced angiogenesis through suppressing the expression of VEGF and Ang1View study →}.

A broad review catalogues antioxidant-linked chemoprevention across multiple tumour models ^{31Reference 31Bagchi et al. · 2014Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overviewView study →}.

Poor absorption means intact OPCs reach the colon at high concentration, which may explain the relatively stronger colorectal signal ^{30Reference 30Huang et al. · 2012Grape seed proanthocyanidins inhibit colon cancer-induced angiogenesis through suppressing the expression of VEGF and Ang1View study →}.

Gap: evidence is entirely preclinical (cell lines, rodent chemoprevention); human cancer-prevention or treatment efficacy has not been shown.

Topical and dietary grape seed proanthocyanidins reduce UV-induced oxidative stress, DNA damage, and immunosuppression in mouse skin and inhibit photocarcinogenesis ^{32Reference 32Katiyar · 2008Grape seed proanthocyanidines and skin cancer prevention: inhibition of oxidative stress and protection of immune systemView study →}, and they feature in reviews of polyphenol photoprotection via anti-inflammatory, antioxidant, and DNA-repair mechanisms ^{33Reference 33Nichols et al. · 2010Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanismsView study →}.

The redox-active fraction also promotes VEGF-driven angiogenesis in experimental dermal wound healing ^{34Reference 34Khanna et al. · 2002Dermal wound healing properties of redox-active grape seed proanthocyanidinsView study →}.

All of it is mouse and cell-culture work; controlled human skin trials are minimal.

Bleeding. Grape seed extract inhibits platelet aggregation by blocking protein tyrosine phosphatases. In mice it reduced platelet aggregation without lengthening bleeding time ^{36Reference 36Jin et al. · 2014Grape seed extracts inhibit platelet aggregation by inhibiting protein tyrosine phosphataseView study →}. It is still sensible to take care with anticoagulant and antiplatelet drugs and to stop it about a week before surgery.

Drug metabolism. Grape seed products inhibit the liver enzymes CYP3A4 and CYP2C9 in laboratory tests, and different brands of the same supplement vary widely in how strongly they do so ^{37,38,43Reference 37Wanwimolruk et al. · 2009Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4View study →Reference 38Mooiman et al. · 2014The effect of complementary and alternative medicines on CYP3A4-mediated metabolism of three different substratesView study →Reference 43Etheridge et al. · 2007In vitroAn in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituentsView study →}.

In heavy active and former smokers, three months of a grape seed procyanidin extract did not change CYP3A4 activity, measured by how the body processes cortisol ^{42Reference 42Xue et al. · 2024The effects of a grape seed procyanidin extract on cytochrome P450 3A4 activity and inflammatory mediators in the lungs of heavy active and former smokersView study →}. No study has yet given a test drug alongside grape seed extract.

Tolerability. In rats the extract’s lethal oral dose was above 5,000 mg/kg, and mice fed it for six to twelve months showed no harmful effects ^{39Reference 39Ray et al. · 2001Acute and long-term safety evaluation of a novel IH636 grape seed proanthocyanidin extractView study →}. Human trials across blood pressure, blood fats, fatty liver and blood sugar report no significant side effects over 4–12 weeks. Long-term human data are lacking.